The term “Taxane” is generally referred to the diterpenes produced from plants of the genus Taxus. The term denotes a compound containing the core structure as in the formula below:

The basic taxane core structure may further be substituted or may contain unsaturations in the ring to yield a number of compounds, generically known as taxanes. The taxane group of drugs includes paclitaxel and docetaxel. Paclitaxel (Taxol®, Bristol Meyers Squibb) is a naturally occurring complex diterpenoid, which was originally isolated from the needles and bark of the Pacific yew tree (Taxus Brevifolia) which is a rare slow-growing tree with limited geographic distribution. The drug was discovered as part of a National Cancer Institute program in which extracts of thousands of plants and natural products were screened for anti-neoplastic activity. Later research led to semi-synthetic preparation of the drug from precursor chemicals called baccatins, which were derived from the needles and twigs of the European or Himalayan yew tree (Taxus Bacatta). Paclitaxel was approved in United States in December 1992 for treatment of patients with metastatic carcinoma of the ovary after failure of first-line or subsequent chemotherapy. It is currently marketed for the treatment of patients with cancer of lung, breast cancer and advanced forms of Kaposi's sarcoma.
Docetaxel (Taxotere®, Sanofi Aventis), which is reportedly the more potent congener of paclitaxel, is the first “taxoid,” i.e., taxol-like compound. The main use of docetaxel is in the treatment of a variety of cancers after the failure of initial chemotherapy. It is marketed towards the treatment of breast cancer, prostate cancer, non-small cell cancer, gastric adenocarcinoma, and squamous cell carcinoma of head and neck. Clinical data has shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal and gastric cancer and melanoma cells (Lyseng-Williamson K. A., Drugs 2005; 65(17):2513-31). Docetaxel has been shown to improve survival as an adjuvant therapy with doxorubicin and cyclophosphamide for the treatment of node-positive breast cancer, and so docetaxel has the benefit of aiding other treatments.
Formula II below represents structure of paclitaxel (R1═H; R2=acetyl; R3=Ph) and docetaxel (R1═H; R2═H; R3=tert-butyloxy)

The conventional numbering system for this class of drugs, which is also followed throughout this application is represented below:

The first-generation taxanes, paclitaxel and docetaxel, are currently considered to be two of the most exciting drugs in cancer chemotherapy. Both of these exhibit significant and broad spectrum anticancer activity against various cancers which have not been effectively treated by other chemotherapeutic drugs. The anticancer activity of these drugs is through a unique mechanism of action which involves binding reversibly to microtubules with high affinity, causing stabilization of the microtubules and preventing their depolymerization from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule, thereby inhibiting cell proliferations. Thus unlike other microtubule poisons such as Vinca alkaloids, colchicines, combretastatins and cryptophycins which inhibit tubulin polymerization, taxanes stabilize microtubules.
Although both paclitaxel and docetaxel have been demonstrated to be unique antitumor agents, there are several limitations to their effectiveness. These include poor selectivity for killing of cancer cells vs. normal cells, development of multidrug resistance (MDR), and poor solubility in the aqueous media which are generally employed for administered drugs. The low aqueous solubility necessitates the preparation of these drugs in non-aqueous medium, for example, a mixture of Cremophor EL® (a polyethoxylated castor oil) and ethanol as co-solvent is used in the dosage forms to solublize paclitaxel. Unfortunately, the high amount of Cremophor EL® required to deliver the indicated dose of paclitaxel exacerbates the side effects of taxol in patients. Weiss et al (J. Clin. Oncol., 1990, 8, 1263-1268) and many others have reported various hypersensitive reactions which include severe skin rashes, hives, flushing, dyspnea and tachycardia in patients treated with such formulation. These effects are attributed partly due to Cremophor EL®, which is responsible for histamine release (Rowinsky, E. K. et al. J. Natl Cancer Inst. 1990; 82, 1247-59). Like paclitaxel, docetaxel (<0.05 mg/mL) is also poorly soluble in water. Currently used the most preferred solvent used for dissolution of docetaxel is polysorbate 80 (Tween® 80). Like Cremophor EL®, the polysorbate also, often causes hypersensitivity reactions in patients. Further, the polysorbate cannot be used with PVC delivery apparatus because of its tendency to leach toxic diethylhexyl phthalate. Thus special provisions are required for the preparation and administration of paclitaxel solutions to ensure safe drug delivery to patients, which inevitably leads to higher costs for the preparation.
Several groups have investigated the synthesis of derivatives, including prodrug forms of taxanes, with a view to improve their aqueous solubility and to develop safer clinical formulations. The studies have been directed at synthesizing taxane analogs wherein 2′- and/or 7 or 10-position is derivatized with suitable groups. These efforts yielded taxane conjugates or protaxanes of reportedly higher aqueous solubility than the parent taxane. Some of the prior art compounds are exemplified in the following references:    U.S. Pat. No. 4,942,184 (Haugwitz R. D. et al.) discloses water soluble taxols having various substituted acyl groups at 2′-O-position;    U.S. Pat. No. 4,960,790 (Stella V. J. et al.) discloses water soluble taxols, the 2′ and/or 7-hydroxy of which is derivatized with a selected amino acid or an amino acid mimetic compound;    U.S. Pat. No. 5,352,805 (1994) and U.S. Pat. No. 5,411,984 (1995) (Kingston David et al.) discloses sulfonated 2′-acryloyl, sulfonated 2′-O-acyl acid taxol and substituted 2′-benzoyl and 2′,7-dibenzoyl taxol which have improved water solubility;    U.S. Pat. No. 5,817,840 (1998) (Nicolaou K C et al.) discloses alkaline sensitive water soluble protaxols, protaxol composition include 2′- and/or 7-O-ester and 2′- and/or 7-O-carbonate derivatives of taxol, which have enhanced water solubility besides increased in vitro cytotoxic activity compared to paclitaxel;    U.S. Pat. No. 5,977,163 (1999) (Chun Li et al.) discloses water soluble taxane derivatives formed by conjugation with polymers such as polyethylene glycol, poly(L-glutamic acid), poly(L-aspartic acid);    PCT application published as WO9414787 (Poss M. A. et al) discloses water soluble prodrug form of taxanes possessing a phosphonoxy group at the C-7, C-10 and/or at the 2′-position of the side chain of a taxane.
Numerous other studies have also been reported in the literature with regard to conjugates of taxanes for improvement of aqueous solubility. These include:    Salts of 2′-succinylpaclitaxel and 2′-glutarylpaclitaxel, Deutsch et al. (J. Med. Chem. 1989, 32, 788-792);    Sulfonate derivatives—Zhao, Z. et al. (J. Nat. Prod. 1991, 54, 1607-1611);    2′ and 7-Amino acid derivatives of paclitaxel and their salts—Mathew et al. (J. Med. Chem. 1992, 35, 145-151);    7-Phosphate paclitaxel analogues—Vyas et al. (Bioorg. Med. Chem. Lett. 1993, 3, 1357-1360);    2′- and 7-Phosphonoxyphenyl-propionate paclitaxel—Ueda, Y. et al. (Bioorg. Med. Chem. Lett. 1993, 3, 1761-1366);    2′ and 7-Polyethylene glycol esters of paclitaxel—Greenwald et al. (J. org. Chem. 1995, 60, 331-336 and J. Med. Chem. 1996, 39, 424-431);    2′- and 7-Methylpyridinium acetate analogues of paclitaxel—Nicholaou K. C. et al. (Angew Chemie 1994, 106, 1672-1675) and Paloma I. G. et al. (Chem. Biol. 1994, 1, 107-112);    Prodrug of paclitaxel with malic acid at the 2′ postion—Damen, E. W. P. et al (Bioorg. Med. Chem. Lett. 2000, 8, 427-432).